The long-term goals for this project are to better understand the role of iron in atherosclerosis and to use this understanding to improve diagnosis of cardiovascular disease. Cardiovascular disease kills 4-6 times more women than breast cancer and despite advances in therapy, mortality has not improved as it has in men. Preventive approaches based, on hormone replacement therapy (HRT), however, have been disappointing, causing increases in stroke and cardiovascular events instead of reductions. Another hypothesis is that the monthly iron loss associated with menses is cardioprotective, and the accumulation of iron after menopause leads to atherosclerosis. Additional motivation to investigate iron in atherosclerosis arises from molecular evidence of iron's role in endothelial cell damage and inflammation as well as epidemiological observations that the incidence of cardiovascular events is greater in states of iron overload. Furthermore, iron catalyzes the generation of free radicals that oxidize cholesterol stimulating atheroma formation. Magnetic resonance imaging (MRI) is ideally suited to study iron because of iron's local effects on magnetic susceptibility, as well as the ability to noninvasively image atheros I erotic plaque with MRI. Careful attention must also be paid the chemistry of iron in atherosclerotic plaque; electron paramagnetic resonance (EPR) spectroscopy imaging may provide unique insights into the forms of iron involved in vascular injury. Thus, significant technologic development must occur before we can begin to study iron in vivo to answer the clinical questions which motivate this research. This proposal is designed to achieve the following specific aims: AIM 1. To develop MRI-based plaque imaging optimized for iron detection in patients with carotid atherosclerosis, using EPR and ICP-MS to validate in vivo noninvasive imaging of vascular iron. AIM 2. To implement the optimized MRI-based iron detection technique in a prospective study of patients undergoing carotid endarterectomy. Subgroup analyses will include comparison of the presence of iron symptomatic versus asymptomatic patients and women versus age-matched men.